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Clinical Pharmacogenetics Implementation
Consortium (CPIC) Guidelines for Codeine
Therapy in the Context of Cytochrome P450 2D6
(CYP2D6) Genotype
KR Crews1, A Gaedigk2, HM Dunnenberger3, TE Klein4, DD Shen5,6, JT Callaghan7,8, ED Kharasch9
and TC Skaar7
Codeine is bioactivated to morphine, a strong opioid agonist,
by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the
efficacy and safety of codeine as an analgesic are governed by
CYP2D6 polymorphisms. Codeine has little therapeutic effect
in patients who are CYP2D6 poor metabolizers, whereas the
risk of morphine toxicity is higher in ultrarapid metabolizers.
The purpose of this guideline (periodically updated at http://
www.pharmgkb.org) is to provide information relating to the
interpretation of CYP2D6 genotype test results to guide the
dosing of codeine.
Focused Literature Review
A systematic literature review was conducted that focused on
CYP2D6 and its relevance in codeine use (see Supplementary
Data online). This guideline was developed based on interpretation of the literature by the authors and by experts in the field.
Gene: Cyp2d6
Background
More than 80 CYP2D6 alleles have been defined by the
Cytochrome P450 Nomenclature Committee at http://www.
cypalleles.ki.se. Clinical phenotype data are available for many
common alleles (see Supplementary Tables S1–S5 online);
however, many alleles are not typically tested for in clinical
trials. Their clinical phenotype is predicted on the basis of the
expected functional impact of their defining genetic variation or
is extrapolated from results of in vitro functional studies using
different substrates.
Interpretation of genetic test results
Most clinical laboratories report CYP2D6 genotype using the
star (*) allele nomenclature and may provide interpretation of
the patient’s predicted metabolizer phenotype. Single-nucleotide
polymorphisms (SNPs) and other sequence variations, including insertions and deletions, are determined by genetic laboratory tests. The reference SNP number (rs number) for a given
SNP defines the specific genomic nucleotide alteration. Each
star (*) allele (or haplotype) is defined by the presence of a specific combination of SNPs and/or other sequence alterations
within the CYP2D6 gene locus. The key alleles are shown in
Supplementary Table S1 online and the key allele-defining
SNPs and their respective impacts on CYP2D6 enzyme function
are provided in Supplementary Table S2 online. Genetic results
are reported as a diplotype, which includes one maternal and
one paternal allele (e.g., CYP2D6*1/*4; Supplementary Table
S3 online). In some cases, patients have more than two copies
of the CYP2D6 gene. Those alleles are denoted by an “xN” following the allele designation (e.g., CYP2D6*2xN; duplication)
(see Supplementary Data online for details). Additional details
about allele nomenclature and definitions can be found at http://
www.cypalleles.ki.se/cyp2d6.htm, and information regarding the
effects of allelic variation on CYP2D6 substrates can be found
at http://www.pharmgkb.org/search/annotatedGene/cyp2d6/
haplotype.jsp. CYP2D6 allele frequencies differ substantially
between racial and ethnic groups. Supplementary Table S1
online summarizes the most important allele frequencies for
the major races and Hispanics.
1Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee, USA; 2Division of Pediatric Pharmacology and Medical
Toxicology, Children’s Mercy Hospital & Clinics, Kansas City, Missouri, USA; 3University of Tennessee College of Pharmacy, Memphis, Tennessee, USA; 4Department of
Genetics, Stanford University, Stanford, California, USA; 5Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA;
6Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, USA; 7Division of Clinical Pharmacology, Department of Medicine,
Indiana University School of Medicine, Indianapolis, Indiana, USA; 8Department of Veterans Affairs, RLR VA Medical Center, Indianapolis, Indiana, USA;
9Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA. Correspondence: KR Crews
([email protected])
Received 1 August 2011; accepted 11 October 2011; advance online publication 28 December 2011. doi:10.1038/clpt.2011.287
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The combination of alleles is used to determine a patient’s
diplotype. CYP2D6 alleles are characterized as wild-type (normal function), reduced-function, or nonfunctional based on the
expected activity level of the enzyme for which they encode.
Each functional group is assigned an activity value ranging
from 0 to 1.0 (e.g., 0 for nonfunctional, 0.5 for reduced function, and 1.0 for fully functional).1 Supplementary Table S4
online describes the activity score values assigned to selected
alleles. If multiple copies of the CYP2D6 gene are detected, the
activity score is multiplied by the number of copies of each allele
present. The total CYP2D6 activity score is the sum of the values
assigned to each allele, which typically ranges from 0 to 3.0 but
may exceed 3.0 in rare cases.1,2
The CYP2D6 activity score relates to the phenotype classification system as follows (Table 1): patients with an activity score of
0 are poor metabolizers, those with a score of 0.5 are considered
intermediate metabolizers, and those with a score of 1.0, 1.5 or 2.0
represent a range of extensive metabolizers. Patients with a score
>2.0 are classified as ultrarapid metabolizers. The extensive metabolizer phenotype represents normal (wild-type) enzyme activity.1–3
The incidence of poor and ultrarapid metabolizers varies greatly
(0–10% and 0–29%, respectively) among various populations.
Selected CYP2D6 activity scores are provided in Supplementary
Table S3 online, and predicted phenotypes of common diplotypes
are summarized in Supplementary Table S5 online.
It is noted that subjects with genotypes giving rise to an activity
score of 1.0, caused by a diplotype containing one functional
and one nonfunctional allele or containing two reduced-function
alleles, are classified by some investigators as “intermediate
metabolizers.” Regardless of the term used to describe such
Table 1 Assignment of likely codeine metabolism phenotypes
based on CYP2D6 diplotypes
Likely phenotypea
Ultrarapid
metabolizer
(~1–2% of patients)
Extensive
metabolizer
(~77–92% of
patients)
Activity
score Genotypes
>2.0
Examples of
diplotypes
An individual carrying *1/*1xN, *1/*2xN
more than two copies of
functional alleles
1.0–2.0b An individual carrying *1/*1, *1/*2, *2/*2,
two alleles encoding full *1/*41,*1/*4,*2/*5,
or reduced function or *10/*10
one full function allele
together with either one
nonfunctional or one
reduced-function allele
Intermediate
metabolizer
(~2–11% of
patients)
0.5b An individual carrying
one reduced and one
nonfunctional allele
*4/*10, *5/*41
Poor metabolizer
(~5–10% of
patients)
0
*4/*4, *4/*5, *5/*5,
*4/*6
An individual carrying
no functional alleles
aThe frequency estimates are based on data from Caucasians and may differ
substantially for other ethnicities. See Supplementary Data online for estimates
of phenotype frequencies among different ethnic/geographic groups. bNote
that some investigators define patients with an activity score of 0.5 and 1.0 as
intermediate metabolizers and define patients with an activity score of 1.5 and 2.0 as
extensive metabolizers. Classifying patients with an activity score of 1.0 as extensive
metabolizers in this guideline is based on data specific for formation of morphine from
codeine in these patients.13
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individuals (extensive metabolizers or intermediate metabolizers), they have lower CYP2D6 activity than subjects with two
fully functional alleles (activity score of 2.0) and higher activity
as compared with subjects with one reduced and one nonfunctional allele (with an activity score of 0.5). Given that there is
no gold standard for phenotype classification, genotypes that
result in CYP2D6 activity scores of 1.0, 1.5, and 2.0 are grouped
together as extensive metabolizers in this guideline, which is
based on data specific for codeine metabolism (Supplementary
Table S6 online).
It should be noted that reference laboratories providing clinical CYP2D6 genotyping may use varying methods to assign phenotypes. Therefore it is advisable to note a patient’s CYP2D6
diplotype and to calculate an activity score before making therapeutic decisions about codeine therapy.
Available Genetic Test Options
Several academic and commercial clinical laboratories offer
genetic testing for CYP2D6. Specific information (on several
of these laboratories, on the assays, and links to the product
labels) can be found in the supplementary information and
at http://www.pharmgkb.org/resources/forScientificUsers/
pharmacogenomic_tests.jsp.
Incidental findings
Currently, there are no diseases or conditions known to be linked
to variations in the CYP2D6 gene independent of drug metabolism and response. Although there are some isolated reports of
CYP2D6 genetic effects on phenotypes other than in relation
to drug response,4,5 these findings have not been consistently
reproduced in other studies.
Other considerations
Modification of the predicted phenotype by drug interactions. The CYP2D6
metabolizer phenotype may undergo alteration in a patient who
is taking drugs that inhibit CYP2D6 activity. A list of CYP2D6
inhibitors can be found at http://medicine.iupui.edu/clinpharm/
ddis/table.aspx. For this purpose, drugs are classified as strong,
moderate, or weak inhibitors, based on the US Food and Drug
Administration (FDA) guidance on drug interaction studies
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/DrugInteractionsLabeling/ucm081177.
htm#classInhibit). Borges et al. demonstrated that incorporating
the impact of drug interactions by CYP2D6 inhibitors improves
the ability of the activity score to predict the extent of tamoxifen
metabolism by CYP2D6.2 For patients on strong inhibitors, the
CYP2D6 activity score is adjusted to 0 and the predicted phenotype is that of a poor metabolizer. For patients who are on weak
or moderate CYP2D6 inhibitors, the activity score is multiplied
by 0.5 and then converted to the predicted phenotype.2
CYP2D6 does not appear to be induced by concurrent medications; however, there are limited data showing that CYP2D6
enzyme activity increases during pregnancy. Wadelius et al.
demonstrated that CYP2D6 activity increases during pregnancy by showing that the value of the dextromethorphan/
dextrorphan metabolic ratio was reduced by 53%; Heikkinen et al.
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demonstrated that the norfluoxetine/fluoxetine metabolic ratio
increased 2.4-fold.6,7 The apparent oral clearance of metoprolol was shown to increase four- to fivefold during pregnancy.8
Although mean CYP2D6 activity appears to increase during
pregnancy, the large interindividual variability in the increase,
and the limited number of subjects studied, make it difficult to
make any recommendations regarding adjustment of the activity scores of functional alleles during pregnancy. The CYP2D6
activity scores of nonfunctional alleles are not affected by pregnancy.
Codeine
Background
Codeine is an opioid analgesic indicated for the relief of mild to
moderately severe pain. The analgesic properties of codeine stem
from its conversion to morphine and morphine-6-glucuronide
because codeine’s affinity for µ-opioid receptors is 200-fold
weaker than that of morphine.9,10 Both codeine and morphine
also have antitussive effects.
O-Demethylation of codeine into morphine by CYP2D6 represents a minor pathway in extensive metabolizers, accounting
for only 5–10% of codeine clearance in such individuals; however, this pathway is essential for its opioid activity (Figure 1).
The percentage of codeine converted into morphine can be
affected by drug interactions and can be much higher in ultrarapid metabolizers.11 Morphine is further glucuronidated
to morphine-3-glucuronide and morphine-6-glucuronide.
Morphine-6-glucuronide is known to have analgesic activity in
humans, whereas morphine-3-glucuronide is generally not considered to possess analgesic properties. Approximately 80% of an
administered dose of codeine is converted to inactive metabolites by glucuronidation to codeine-6-glucuronide via UDPglucuronosyltransferase (UGT) 2B7, and by N-demethylation
to norcodeine via CYP3A4. The analgesic activity of codeine6-glucuronide in humans is unknown, whereas norcodeine is
thought to have no analgesic properties.
Codeine analgesia is closely related to CYP2D6 pharmacogenetics. The association between CYP2D6 metabolizer phenotype and the formation of morphine from codeine is well
defined. Pharmacokinetic and pharmacodynamic studies show
a decrease in morphine levels and a decrease in analgesia in
Codeine
CYP3A4
CYP2D6
Morphine
Norcodeine
UGT2B7
UGT2B7
UGT1A1
Morphine-3-glucuronide
UGT2B7
Codeine-6-glucuronide
UGT1A1
Morphine-6-glucuronide
Normorphine
Figure 1 Codeine metabolism pathway.
poor metabolizers receiving codeine as compared with extensive
metabolizers.12,13 Mikus et al. reported a decreased incidence of
gastrointestinal side effects (i.e., constipation) in poor metabolizers as compared with extensive metabolizers;14 a later study by
the same group of investigators found that central side effects
(e.g., sedation, nausea, and dry mouth) did not differ between
poor metabolizers and extensive metabolizers.12 Further studies
are needed to fully investigate the impact of the CYP2D6 poor
metabolizer phenotype on the adverse-effect profile of codeine.
On the other hand, increased conversion to morphine in
CYP2D6 ultrarapid metabolizers can result in toxic systemic
concentrations of morphine11 even at low codeine doses. The
most common adverse reactions to codeine include drowsiness,
lightheadedness, dizziness, sedation, shortness of breath, nausea,
vomiting, and sweating. Serious adverse reactions include respiratory depression and, to a lesser degree, circulatory depression,
respiratory arrest, shock, and cardiac arrest. Pharmacokinetic
studies show increased conversion of codeine to morphine in
ultrarapid metabolizers as compared with extensive metabolizers.15 Case reports detail the occurrence of severe or lifethreatening side effects following standard doses of codeine in
ultrarapid metabolizers.11,16,17
Despite these data, codeine continues to be widely used, and
most patients receive codeine without prior CYP2D6 genotyping. This guideline recommends using alternative analgesics
in patients who are CYP2D6 poor metabolizers or ultrarapid
metabolizers. It is important to recognize that, in addition to
codeine, several other opioids are metabolized, at least in part,
by CYP2D6. The opioids tramadol, hydrocodone, and oxycodone are O-demethylated by CYP2D6 to O-desmethyltramadol,
hydromorphone, and oxymorphone, respectively.
Tramadol in its available racemic form is extensively metabolized
via several pathways, including CYP2D6-mediated oxidation to
O-desmethyltramadol, which has a 200-fold greater affinity for
µ-opioid receptors than the parent drug does.10,18 Consequently,
(+)-O-desmethyltramadol is principally responsible for opioid
receptor-mediated analgesia, whereas (+)- and (−)-tramadol
contribute to analgesia by inhibiting reuptake of the neurotransmitters serotonin and noradrenaline. As compared with
CYP2D6 extensive metabolizers, poor metabolizers have been
shown to have much lower median values of area under the
concentration–time curves for the active metabolite after a dose
of tramadol.19,20 In addition, several prospective clinical trials
have shown that, as compared with CYP2D6 extensive metabolizers, poor metabolizers more often fail to exhibit analgesia in
response to tramadol.18,19,21 Judging from this evidence, it is
likely that tramadol has reduced clinical efficacy in CYP2D6
poor metabolizers.
Pharmacokinetic studies showed higher peak plasma concentrations of (+)-O-desmethyltramadol after a dose of tramadol,
and also greater analgesia, stronger miosis, and higher incidence
of nausea in ultrarapid metabolizers as compared with extensive
metabolizers.22 There is one case report of respiratory depression in a CYP2D6 ultrarapid metabolizer with renal impairment after postsurgical tramadol treatment.23 On the basis of
these data, the use of analgesics other than tramadol may be
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preferable in CYP2D6 poor metabolizers and also in ultrarapid
metabolizers.
Hydrocodone is biotransformed by CYP2D6 into hydromorphone, which has a 10- to 33-fold greater affinity for μ-opioid
receptors as compared with the parent drug. Relative to extensive metabolizers, poor metabolizers have been shown to have
lower peak concentrations of hydromorphone after a dose of
hydrocodone24; however, CYP2D6 metabolizer status does not
appear to affect response to hydrocodone.24,25 To date, there
is no information on the pharmacokinetics of hydrocodone in
CYP2D6 ultrarapid metabolizers. Therefore, there is insufficient
evidence as to whether poor metabolizers can be expected to
have decreased analgesia when treated with hydrocodone, and
whether ultrarapid metabolizers have an increased risk of toxicity with normal doses of hydrocodone.
Approximately 11% of an oxycodone dose is O-demethylated
by CYP2D6 to the minor metabolite oxymorphone, which has a
40-fold higher affinity and eightfold higher potency for µ-opioid
receptors as compared with the parent drug.10,26 As compared
with extensive metabolizers, poor metabolizers have been shown
to have lower peak concentrations of oxymorphone after a dose
of oxycodone.27,28 However, prospective clinical studies have
produced conflicting data pertaining to the associations between
CYP2D6 metabolizer phenotype and the analgesic effect and toxicity of oxycodone. In two studies in healthy volunteers, differential analgesia response to experimental pain stimuli was observed
between extensive and poor metabolizers and also between
ultrarapid and extensive/poor metabolizers.29,30 However, clinical studies in postoperative patients and in patients with cancer
failed to demonstrate a significant difference in analgesia or side
effects in response to oxycodone across CYP2D6 phenotypes.27,28
Physiologic alterations (e.g., miosis) after dosing with oxycodone
correlate best with exposure to the parent compound.31 It is
therefore premature to recommend routine therapy adjustment
for oxycodone on the basis of CYP2D6 genotype.
The differing levels of evidence for the association of
CYP2D6 phenotype with hydrocodone and oxycodone analgesia as compared with codeine and tramadol may be because
of the difference in the relative roles of the parent drug and
circulating metabolites in analgesia among these CYP2D6
substrates.31
To avoid treatment complications, opioids that are not
metabolized by CYP2D6, including morphine, oxymorphone,
buprenorphine, fentanyl, methadone, and hydromorphone,32
along with nonopioid analgesics, may be considered as alternatives for use in CYP2D6 poor metabolizers and in ultrarapid
metabolizers, depending on the type and chronicity of the pain
being treated.
Other genes affecting codeine
Glucuronidation of codeine and of morphine is mediated by
the polymorphic UGT2B7 enzyme.33 Although the production
of morphine-6-glucuronide is almost exclusively catalyzed by
UGT2B7, several isoforms of the UGT1A subfamily are also
involved in the formation of morphine-3-glucuronide. Conflicting
evidence exists regarding the impact of the UGT2B7*2
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variant on the glucuronidation of codeine.34 Polymorphisms in
the MDR1 transporter (ABCB1) gene also appear to have a
modest association with opioid dose requirements.35 The
response to codeine may also be influenced by polymorphisms
in drug response genes including, but not limited to, the opioid
receptor µ1 gene OPRM1; however, the importance of this gene
to clinical outcome is not yet fully appreciated.35
Linking Genetic Variability To Variability in
Drug-Related Phenotypes
There is substantial evidence linking CYP2D6 genotype to
variability in codeine efficacy and toxicity (see Supplementary
Table S6 online). Decreased codeine analgesia has been
observed in poor metabolizers, whereas severe or life-threatening toxicity after normal doses of codeine has been documented
in ultrarapid metabolizers. This body of evidence, rather than
randomized clinical trials involving pharmacogenetic testing, provides the basis of the therapeutic recommendations in
Table 2.
Table 2 Codeine therapy recommendations based on CYP2D6
phenotype
Phenotype
Implications
for codeine
metabolism
Classification of
Recommendations recommendation
for codeine
for codeine
therapya
therapy
Ultrarapid
Increased formation
metabolizer of morphine
following codeine
administration,
leading to higher
risk of toxicity
Avoid codeine use Strong
due to potential for
toxicity. Consider
alternative
analgesics such
as morphine or a
nonopioid. Consider
avoiding tramadol.b
Extensive
Normal morphine
metabolizer formation
Strong
15–60 mg every
4 h as needed
for pain (label
recommendation)
Intermediate Reduced morphine Begin with 15–60 Moderate
metabolizer formation
mg every 4 h as
needed for pain.
If no response,
consider alternative
analgesics such
as morphine or a
nonopioid. Monitor
tramadol use for
response.
Poor
Greatly reduced
metabolizer morphine formation
following codeine
administration,
leading to
insufficient pain
relief
Avoid codeine
Strong
use due to lack of
efficacy. Consider
alternative
analgesics such
as morphine or a
nonopioid. Consider
avoiding tramadol.b
aRating scheme is described in Supplementary Data online. bAlthough detailed
recommendations for using CYP2D6 phenotype in tramadol therapy are beyond the
scope of this guideline, there is strong evidence for decreased efficacy of tramadol in
poor metabolizers and a single case report of toxicity in an ultrarapid metabolizer with
renal impairment following tramadol postsurgery. Use of other analgesics in CYP2D6
poor metabolizers and ultrarapid metabolizers may therefore be preferable.18,19,21,23
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Cyp2d6 Genetic Test Interpretation and Suggested
Clinical Action
Table 2 summarizes the therapeutic recommendations for
codeine based on CYP2D6 phenotype. A standard starting
dose of codeine, as recommended in the product label, is warranted in patients with an extensive metabolizer phenotype
(i.e., a CYP2D6 activity score of 1.0 to 2.0). Likewise, a standard starting dose of codeine is warranted in patients with an
intermediate metabolizer phenotype (i.e., a CYP2D6 activity
score of 0.5); these patients should be monitored closely for
less than optimal response and should be offered an alternative analgesic if required. If the CYP2D6 substrate tramadol is
selected as alternative therapy in intermediate metabolizers,
close monitoring should be carried out because of the possibility of low response.
If clinical genotyping identifies a patient as a CYP2D6 poor
metabolizer (i.e., a CYP2D6 activity score of 0), current evidence suggests that the use of codeine be avoided because of
the possibility of lack of effect, and that an alternative analgesic
should be used. That is, it may be preferable to use an analgesic
other than the CYP2D6 substrate tramadol in poor metabolizers. There is insufficient evidence in the literature to recommend
a higher dose of codeine in poor metabolizers, especially given
that adverse effects do not differ between poor metabolizers and
extensive metabolizers.12
In a patient identified as a CYP2D6 ultrarapid metabolizer
(i.e., a CYP2D6 activity score of >2.0), the choice of an alternative analgesic should be made to avoid the risk of severe toxicity
associated with a “normal” dose of codeine. That is, it may be
preferable to use an analgesic other than the CYP2D6 substrate
tramadol in ultrarapid metabolizers.
Other Considerations: Breastfed Infants
Codeine and its metabolites, including morphine, are secreted
in human breast milk, but the amount is typically low and dose
dependent. However, breastfeeding women with an ultrarapid metabolizer phenotype may achieve high serum levels
of morphine on standard codeine therapy.36 This may lead to
high concentrations of morphine in breast milk and dangerously high serum morphine levels in their breastfed infants.37
Notably, there was a reported case of fatal opioid poisoning in
a breastfed neonate as a result of the codeine treatment taken
by the mother, an ultrarapid metabolizer.38 Case reports such
as this prompted the FDA to change the codeine product label
to include information on the increased risk of morphine overdose in breastfed infants whose mothers are taking codeine
and are ultrarapid metabolizers. Additional information about
codeine use in breastfeeding mothers can be found elsewhere.39
Codeine is not recommended in children less than 2 years
of age and presumably would carry similar dangers in other
neonates and young children who are themselves ultrarapid
metabolizers.17
Potential Benefits and Risks For the Patient
The potential benefit of CYP2D6 genotype testing is that
patients with genotypes that are associated with a higher
risk of ineffective analgesia or of an adverse event may be
identified, and alternative analgesics may be administered
to these patients. CYP2D6 genotyping is reliable when
performed in qualified laboratories. However, as with any
laboratory test, a possible area of risk is an error in genotyping,
which could have long-term adverse health implications for
the patient.
Caveats: Appropriate Use and/Or Potential Misuse
of Genetic Tests
One of the challenges with using clinical pharmacogenetic testing for codeine dosing is the need for results at the time an analgesic regimen is chosen. The ideal situation is to preemptively
genotype patients who may need pain control in the future. For
instance, preemptive CYP2D6 genotyping has been implemented
in patients treated for acute lymphoblastic leukemia, who often
require pain control medication during their therapy.40 Like all
diagnostic tests, the CYP2D6 genotype test is one of multiple
pieces of information that clinicians should consider in guiding
their therapeutic choice for each patient.
Disclaimer
Clinical Pharmacogenetics Implementation Consortium (CPIC)
guidelines reflect expert consensus based on clinical evidence
and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making
and to identify questions for further research. New evidence may
have emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to
interventions or diseases not specifically identified. Guidelines
do not account for all individual variations among patients and
cannot be considered inclusive of all proper methods of care or
exclusive of other treatments. It remains the responsibility of
the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary,
with the ultimate determination regarding its application to be
made solely by the clinician and the patient. CPIC assumes no
responsibility for any injury to persons or damage to persons or
property arising out of or related to any use of CPIC’s guidelines,
or for any errors or omissions.
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at
http://www.nature.com/cpt
Acknowledgments
We acknowledge the critical input of S. Cross, H.J. Guchelaar, J. Hoffman,
T. Manolio, P. Mummaneni, M. Relling, and S. Scott and members of
the Clinical Pharmacogenetics Implementation Consortium of the
Pharmacogenomics Research Network, funded by the National Institutes
of Health (NIH). This work was supported by NIH U01 GM061373, R01
GM088076, K24DA00417, PharmGKB (R24-GM61374), ALSAC, and the
Agency for Healthcare Research and Quality R01 HS19818-01. The content
is solely the responsibility of the authors and does not necessarily represent
the official views of the Agency for Healthcare Research and Quality.
Conflict of Interest
The authors declared no conflict of interest.
© 2012 American Society for Clinical Pharmacology and Therapeutics
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1. Gaedigk, A., Simon, S.D., Pearce, R.E., Bradford, L.D., Kennedy, M.J. & Leeder, J.S.
The CYP2D6 activity score: translating genotype information into a qualitative
measure of phenotype. Clin. Pharmacol. Ther. 83, 234–242 (2008).
2. Borges, S. et al. Composite functional genetic and comedication CYP2D6
activity score in predicting tamoxifen drug exposure among breast cancer
patients. J. Clin. Pharmacol. 50, 450–458 (2010).
3. Gaedigk, A., Gotschall, R.R., Forbes, N.S., Simon, S.D., Kearns, G.L. &
Leeder, J.S. Optimization of cytochrome P4502D6 (CYP2D6) phenotype
assignment using a genotyping algorithm based on allele frequency data.
Pharmacogenetics 9, 669–682 (1999).
4. Kirchheiner, J., Lang, U., Stamm, T., Sander, T. & Gallinat, J. Association of
CYP2D6 genotypes and personality traits in healthy individuals. J. Clin.
Psychopharmacol. 26, 440–442 (2006).
5. Zackrisson, A.L., Lindblom, B. & Ahlner, J. High frequency of occurrence of
CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism
among suicide cases. Clin. Pharmacol. Ther. 88, 354–359 (2010).
6. Wadelius, M., Darj, E., Frenne, G. & Rane, A. Induction of CYP2D6 in pregnancy.
Clin. Pharmacol. Ther. 62, 400–407 (1997).
7. Heikkinen, T., Ekblad, U., Palo, P. & Laine, K. Pharmacokinetics of fluoxetine and
norfluoxetine in pregnancy and lactation. Clin. Pharmacol. Ther. 73, 330–337
(2003).
8. Högstedt, S., Lindberg, B., Peng, D.R., Regårdh, C.G. & Rane, A. Pregnancyinduced increase in metoprolol metabolism. Clin. Pharmacol. Ther. 37,
688–692 (1985).
9. Mignat, C., Wille, U. & Ziegler, A. Affinity profiles of morphine, codeine,
dihydrocodeine and their glucuronides at opioid receptor subtypes.
Life Sci. 56, 793–799 (1995).
10. Volpe, D.A. et al. Uniform assessment and ranking of opioid Mu receptor
binding constants for selected opioid drugs. Regul. Toxicol. Pharmacol. 59,
385–390 (2011).
11. Gasche, Y. et al. Codeine intoxication associated with ultrarapid CYP2D6
metabolism. N. Engl. J. Med. 351, 2827–2831 (2004).
12. Eckhardt, K., Li, S., Ammon, S., Schänzle, G., Mikus, G. & Eichelbaum, M. Same
incidence of adverse drug events after codeine administration irrespective of
the genetically determined differences in morphine formation. Pain
76, 27–33 (1998).
13. Lötsch, J., Rohrbacher, M., Schmidt, H., Doehring, A., Brockmöller, J. &
Geisslinger, G. Can extremely low or high morphine formation from codeine
be predicted prior to therapy initiation? Pain 144, 119–124 (2009).
14. Mikus, G. et al. Effect of codeine on gastrointestinal motility in relation to
CYP2D6 phenotype. Clin. Pharmacol. Ther. 61, 459–466 (1997).
15. Kirchheiner, J. et al. Pharmacokinetics of codeine and its metabolite morphine
in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J.
7, 257–265 (2007).
16. Dalén, P., Frengell, C., Dahl, M.L. & Sjöqvist, F. Quick onset of severe abdominal
pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther. Drug
Monit. 19, 543–544 (1997).
17. Ciszkowski, C., Madadi, P., Phillips, M.S., Lauwers, A.E. & Koren, G. Codeine,
ultrarapid-metabolism genotype, and postoperative death. N. Engl. J. Med.
361, 827–828 (2009).
18. Poulsen, L., Arendt-Nielsen, L., Brøsen, K. & Sindrup, S.H. The hypoalgesic effect
of tramadol in relation to CYP2D6. Clin. Pharmacol. Ther. 60, 636–644 (1996).
19. Stamer, U.M., Musshoff, F., Kobilay, M., Madea, B., Hoeft, A. & Stuber, F.
Concentrations of tramadol and O-desmethyltramadol enantiomers
in different CYP2D6 genotypes. Clin. Pharmacol. Ther. 82, 41–47
(2007).
20. Borlak, J., Hermann, R., Erb, K. & Thum, T. A rapid and simple CYP2D6
genotyping assay–case study with the analgetic tramadol. Metab. Clin. Exp.
52, 1439–1443 (2003).
21. Stamer, U.M. et al. Impact of CYP2D6 genotype on postoperative tramadol
analgesia. Pain 105, 231–238 (2003).
326
22. Kirchheiner, J., Keulen, J.T., Bauer, S., Roots, I. & Brockmöller, J. Effects of the
CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics
of tramadol. J. Clin. Psychopharmacol. 28, 78–83 (2008).
23. Stamer, U.M., Stüber, F., Muders, T. & Musshoff, F. Respiratory depression with
tramadol in a patient with renal impairment and CYP2D6 gene duplication.
Anesth. Analg. 107, 926–929 (2008).
24. Otton, S.V., Schadel, M., Cheung, S.W., Kaplan, H.L., Busto, U.E. & Sellers, E.M.
CYP2D6 phenotype determines the metabolic conversion of hydrocodone to
hydromorphone. Clin. Pharmacol. Ther. 54, 463–472 (1993).
25. Kaplan, H.L. et al. Inhibition of cytochrome P450 2D6 metabolism of
hydrocodone to hydromorphone does not importantly affect abuse liability.
J. Pharmacol. Exp. Ther. 281, 103–108 (1997).
26. Davis, M.P., Varga, J., Dickerson, D., Walsh, D., LeGrand, S.B. & Lagman, R.
Normal-release and controlled-release oxycodone: pharmacokinetics,
pharmacodynamics, and controversy. Support. Care Cancer 11, 84–92
(2003).
27. Zwisler, S.T., Enggaard, T.P., Mikkelsen, S., Brosen, K. & Sindrup, S.H. Impact of
the CYP2D6 genotype on post-operative intravenous oxycodone analgesia.
Acta Anaesthesiol. Scand. 54, 232–240 (2010).
28.Andreassen, T.N. et al. Do CYP2D6 genotypes reflect oxycodone requirements
for cancer patients treated for cancer pain? A cross-sectional multicentre
study. Eur. J. Clin. Pharmacol. (2011).
29. Zwisler, S.T. et al. The hypoalgesic effect of oxycodone in human experimental
pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin.
Pharmacol. Toxicol. 104, 335–344 (2009).
30. Samer, C.F. et al. Genetic polymorphisms and drug interactions modulating
CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic
efficacy and safety. Br. J. Pharmacol. 160, 919–930 (2010).
31. Lalovic, B., Kharasch, E., Hoffer, C., Risler, L., Liu-Chen, L.Y. & Shen, D.D.
Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy
human subjects: role of circulating active metabolites. Clin. Pharmacol. Ther.
79, 461–479 (2006).
32. Rollason, V., Samer, C., Piguet, V., Dayer, P. & Desmeules, J. Pharmacogenetics of
analgesics: toward the individualization of prescription. Pharmacogenomics 9,
905–933 (2008).
33. Coffman, B.L., King, C.D., Rios, G.R. & Tephly, T.R. The glucuronidation of
opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and
UGT2B7H(268). Drug Metab. Dispos. 26, 73–77 (1998).
34. Court, M.H. et al. Evaluation of 3’-azido-3’-deoxythymidine, morphine,
and codeine as probe substrates for UDP-glucuronosyltransferase
2B7 (UGT2B7) in human liver microsomes: specificity and influence of
the UGT2B7*2 polymorphism. Drug Metab. Dispos. 31, 1125–1133
(2003).
35. Lötsch, J. et al. Cross-sectional analysis of the influence of currently known
pharmacogenetic modulators on opioid therapy in outpatient pain centers.
Pharmacogenet. Genomics 19, 429–436 (2009).
36. Willmann, S., Edginton, A.N., Coboeken, K., Ahr, G. & Lippert, J. Risk to
the breast-fed neonate from codeine treatment to the mother:
a quantitative mechanistic modeling study. Clin. Pharmacol. Ther. 86,
634–643 (2009).
37. Madadi, P. et al. Pharmacogenetics of neonatal opioid toxicity following
maternal use of codeine during breastfeeding: a case-control study. Clin.
Pharmacol. Ther. 85, 31–35 (2009).
38. Koren, G., Cairns, J., Chitayat, D., Gaedigk, A. & Leeder, S.J. Pharmacogenetics
of morphine poisoning in a breastfed neonate of a codeine-prescribed
mother. Lancet 368, 704 (2006).
39. Madadi, P. et al. Guidelines for maternal codeine use during breastfeeding.
Can. Fam. Physician 55, 1077–1078 (2009).
40. Crews, K.R. et al. Development and implementation of a pharmacistmanaged clinical pharmacogenetics service. Am. J. Health. Syst. Pharm. 68,
143–150 (2011).
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